Cancer continues to be one of the foremost health problems. Conventional treatments such as surgery, radiation therapy and chemotherapy have been extremely successful in certain cases; in other instances, much less so. A much less familiar, alternative form of cancer therapy known as Boron Neutron Capture Therapy (BNCT) is being investigated to treat certain tumors for which the conventional methods are to date ineffective. BNCT has been used clinically in Japan to treat Glioblastoma multiforme, a highly malignant, invasive form of brain cancer.
In BNCT of malignant brain tumors, the patient is injected with a boron compound highly enriched in boron-10. The boronated compound concentrates preferentially in the brain tumor, while the action of the blood-brain barrier prevents its entry into the healthy surrounding tissues. The patient's head is then irradiated with a beam of thermal neutrons that are captured by the boron concentrated in the tumor. The tumor is thus irradiated with high LET alpha and Li particles whose range in tissue is about 10.mu., or the diameter of an average cell. Therefore, a very localized, specific reaction takes place whereby the tumor receives a large radiation dose, compared to that received by the surrounding healthy tissue, from the transit of the thermal neutrons.
Several criteria must be met in order for BNCT to be successful. These include:
(1) the boron must be in high concentration at the tumor site (about 30 .mu.g.sup.10 B/g tissue);
(2) there should be high selectivity of the drug for tumor over blood with tumor-to-blood ratios greater than two; and
(3) the boronated drug itself should not be toxic. The second criteria above can usually be satisfied if the boronated drug does not penetrate the normal blood brain barrier.
In the clinical practice of BNCT in Japan to treat glioblastoma, Na.sub.2 B.sub.12 H.sub.11 SH (BSH) is used as the boron-containing drug. However, in vitro experiments show that BSH does not stay in the tumor cell but is easily washed out, which may account for the lack of success in some of the trials with this material.
Porphyrins, in contrast, are retained in tumors for days to weeks and have an affinity for various types of cancers. It is therefore an object of this invention to provide new boronated drugs for BNCT that overcome the problems of the prior art materials and that take advantage of these characteristics of the porphyrin molecule.
U.S. Pat. No. 4,516,535 (Russell, Jr., et al) provides a broadly defined disclosure relating to the tumor affinity agent and the source of radioactivity used in BNCT, but only employs a boron hydride cage.
U.S. Pat. No. 4,500,507 (Wong) discloses technetium-labeled porphyrin and its use as a radio-active tracer in scintographic imaging techniques.
U.S. Pat. Nos. 4,675,338 (Bommer, et al) and 4,693,885 (Bommer, et al) are two of many patents which disclose novel porphyrin compounds for use as photosensitive agents in the treatment of tumors.
U.S. Pat. No. 2,858,320 (Woods, et al) discloses the use of hematoporphyrin in delineating cancerous tissue.
U.S. Pat. No. 4,386,087 (Lavallee) discloses N-methyl porphyrin and its use in the chemotherapeutic treatment of cancer.
The present invention is directed to new low toxicity boronated porphyrin compounds and a method for their use in BNCT. A process for preparing the boronated porphyrin compounds and compositions containing such compounds are also disclosed. These porphyrin compounds can be employed as vehicles for the transport of boron to malignant tumors especially brain tumors. The blood-brain barrier in mammals excludes the uptake of boronated porphyrin in normal brain cells and allows accumulation of said porphyrins in tumorous cells, so that upon irradiation significant damage will be done to the tumor cells while little damage will be done to the healthy surrounding tissue.